The structural and functional role of myelin fast-migrating cerebrosides: pathological importance in multiple sclerosis

Abstract

A family of neutral glycosphingolipids containing a 3-O-acetyl-sphingosine galactosylceramide (3-SAG) has been characterized. Seven new derivatives of galactosylceramide (GalCer), designated as fast-migrating cerebrosides (FMCs) by TLC retention factor, have been identified. The simplest compounds - FMC-1 and FMC-2 - of this series have been characterized as the 3-SAG containing nonhydroxy and hydroxy fatty acyl, respectively. The next two - FMC-3 and FMC-4 - add 6-O-acetyl-galactose and the most complex glycosphingolipids, FMC-5, -6 and -7, are 2,3,4,6-tetra-O-acetyl-3-SAG. These hydrophobic myelin lipid biomarkers coappear with GalCer during myelinogenesis and disappear along with GalCer in de- or dys-myelinating disorders. Myelin lipid antigens, including FMCs, are keys to myelin biology, opening the possibility of new and novel immune modulatory tools for treatment of autoimmune diseases including multiple sclerosis.

Figure 1. A composite diagram summarizing features of CNS myelin

(A) Architecture of CNS myelin showing an oligodendrocyte and myelin sheath in CNS. This is a simplified version with fewer myelin sheaths per oligodendrocyte than normal. The cutaway view shows a multilayer membrane (only a few drawn for clarity) formed by oligodendrocytes. (B) Molecular composition of CNS myelin (three-dimensional view). Hypothetical arrangement of protein (20%) and lipids (80%) in the myelin multilayer membrane. Proteins (PLP, MBP, MOG, MAG and CNP) are marked in yellow and the comprising lipids are indicated as follows: cholesterol in orange, phospholipids in pink and the glycosphingolipids in blue. CNP: 2′3′-cyclic-nucleotide 3′-phosphodiesterase; FMC: Fast-migrating cerebroside; GalCer: Galactosylceramide; GM₁: Monosialoganglioside; GM₄: Sialosylgalactosylceramide; MAG: Myelin-associated glycoprotein; MBP: Myelin basic protein; MOG: Myelin oligodendrocyte glycoprotein; PLP: Proteolipid protein; sGalCer: Sulfatide. Adapted and modified from [11] with permission from SAGE Publications.

Figure 2. Myelin O-acetyl galactosylceramide series structures

Galactosylceramide: R1 = H, R2 = H, R3-R6 = H. FMC-1: R1 = H, R2 = Ac, R3-R6 = H; FMC-2: R1 = OH, R2 = Ac, R3-R6 = H; FMC-3: R1 = H, R2 = Ac, R3 = Ac, R4-R6 = H; FMC-4: R1 = OH, R2 = Ac, R3 = Ac, R4-R6 = H; FMC-5: R1 = H, R2-R6 = Ac; FMC-6: R1 = OH, R2-R6 = Ac; FMC-7: R1 = OAc, R2-R6 = Ac. AC: Acetyl; FMC: Fast-migrating cerebroside.

Figure 3. Features of T cells and natural killer^† cells included in natural killer receptor-positive T-cell, natural killer T-cell and invariant natural killer T-cell subsets

As for classical T cells, the NKR⁺ T cells coexpress a TCR and cell surface receptors that are characteristic of the NK cell lineage. NKR⁺ T cells constitute heterogeneous cell populations that represent a significant proportion of the total T-cell population. These cells are found in liver, bone marrow, spleen and GI tract and account for 35–50% of lymphocytes in these organs [200,201]. Based on their TCRs, these cells can be divided into at least two subsets: one that uses an invariant TCR receptor (invariant NKT cells) and a second with a diverse TCR (NKT cells). Invariant NKT cells constitute the low frequency of CD1d-restricted NKT cells that express NK cell surface receptors and highly restricted TCR repertoire encoded by Vα24 and Jα18 genes in humans are homologous to that encoded by Vα14 and Jα18 genes in mice. The majority are heterogeneous and coexpress other TCRs and various NK receptors, including CD56, CD94 and CD161. ^†For clarity, only NK receptors are indicated. NK: Natural killer; NKR⁺: Natural killer receptor-positive; TCR: T-cell receptor.

Figure 4. N-palmitoyl-galactosylceramide with galactose linked in either

α (A) or β (B) configuration to ceramide backbone. β-linked forms of galactosylceramides (and glucosylceamides) are normal constituents of mammals, but α-linked forms are not. The α-linked form of galactosylceramides is found in Agelas mauritianus, a marine sponge. This glycolipid and its synthetic analog, KRN7000, have been used as specific activators of natural killer cells that are involved in the regulation of certain autoimmune diseases [210].